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© 2006 Betterchem Corp.
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Approval Date:
September 15, 1986
Freedom of
Information Summary
NADA 138-703
I. GENERAL INFORMATION:
| NADA |
138-703 |
| Sponsor: |
A.L. Laboratories, Inc.
One Executive Drive
PO Box 1399
Fort Lee, NJ 07024 |
| Generic Name: |
Bacitracin Zinc, Roxarsone and Monensin Sodium
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| Trade Name: |
Albac®, 3-Nitro® and Coban®
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| Marketing Status: |
OTC
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II. INDICATIONS FOR USE
For improved feed efficiency and as an aid in prevention of coccidiosis caused
by Eimeria necatrix, E. tenella, E. acervulina, E. brunetti, E. maxima,
and E. mivati.
III. DOSAGE
| A. |
DOSAGE FORM |
Medicated finished feeds manufactured from approved separate
feed additive premixes for broiler chickens.
Albac®, each pound of premix contains 50 grams bacitracin activity.
3-Nitro® , each pound of premix contains either 45.5, 90.9, 227.3
or 363.6 grams roxarsone.
Coban®, each pound of premix contains 45 grams monensin as monensin
sodium. |
| B. |
ROUTE OF ADMINISTRATION |
For oral administration via the feed for growing broiler chickens.
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| C. |
RECOMMENDED DOSAGES: |
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Bacitracin Zinc: |
4-50 grams per ton |
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Roxarsone |
22.7-45.4 grams per ton (0.0025%-0.005%) |
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Monensin Sodium: |
90-110 grams per ton
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IV. EFFECTIVENESS
Floor Pen Studies
Three floor pen experiments were conducted using approved protocols and 5,640
broiler chickens. Bacitracin zinc was used at 0 or 50 g/ton of feed in
combination with roxarsone at 0 or 45.4 g/ton of feed to provide all 4 possible
combinations of these 2 drugs. Monensin sodium at 110 g/ton was included in all
experimental diets. The experiments were designed to test the effects of
bacitracin zinc and roxarsone in combination with monensin on body weight gains
and feed efficiency. A description of the three experiments follows:
Experiment No. TX-B-112-83
Investigator:
William F. Krueger, Ph.D.
Department of Poultry Science
Texas A&M University
College Station, TX 77843
Monitor:
Ralph V. Fell, Ph.D.
Route 9, Box 42
Pine Bluff, AR 71603
This 47-day experiment was conducted in a conventional type broiler house at
the poultry research facilities, Texas A&M University, College Station, TX
from January 6, 1984 to February 15, 1984. The experiment consisted of four
dietary treatments which were monensin at 110 g/ton, monensin at 110 g/ton plus
bacitracin zinc at 50 g/ton, monensin at 110 g/ton plus roxarsone at 45.4 g/ton
and monensin at 110 g/ton plus bacitracin zinc at 50 g/ton plus roxarsone at
45.4 g/ton. Three thousand day-old, sexed, Cobb x Hubbard Commercial broiler
chicks from one hatchery supply flock were placed randomly by sex in 30 pens to
provide 50 male and 50 female chicks per pen. Treatments were randomly
assigned to blocks of pens. Each 8' x 10' pen was identically equipped with a
six foot mechanical waterer and hand feeders. The pens had dirt floors covered
with used litter and topped with an inch layer of fresh pine shavings. Each pen
had its own artificial light source of a 40 watt light bulb. Artificial light
was provided for 22 hours of total light per day.
Experiment No. MO-B-114-84
Investigator:
Randall A. Primo
Ponderosa Research Company
French
Village, MO 63036
Monitor:
Ralph V. Fell, Ph.D.
Route 9, Box 42
Pine Bluff, AR 71603
This 48-day experiment was conducted from December 16, 1983 to February 2, 1984
in a conventional, insulated, curtain-sided broiler house with poultry wire
partitions and dirt floors at the Ponderosa Research Company facilities. The
experiment consisted of four dietary treatments which were monensin at 110
g/ton, monensin at 110 g/ton plus bacitracin zinc at 50 g/ton, monensin at 110
g/ton plus roxarsone at 45.4 g/ton and monensin at 110 g/ton plus bacitracin
zinc at 50 g/ton plus roxarsone at 45.4 g/ton. Twelve hundred day-old, sexed
broiler chicks were placed randomly by sex in 24 pens to provide 25 male and 25
female chicks per pen. Treatments were randomly assigned to blocks of pens. The
four dietary treatments were then randomly assigned. Each 5'x 8' pen was
identically equipped with a Mono-Flo automatic water fountain, a cylindrical
tube-type hanging self feeder and a thermostatically controlled heat lamp
brooder. Natural light was supplement by a 25 watt bulb over each pen.
Experiment ARK-B-120-84
Investigator:
Park W. Waldroup, Ph.D.
Department of Animal Sciences
University of Arkansas
Fayetteville, AR 72701
Monitor:
Ralph V. Fell, Ph.D.
Route 9, Box 42
Pine Bluff, AR 71603
This 49-day experiment was conducted in a conventional steel-truss building
with insulated roof and side walls, a 3 foot curtain and automatic fans at the
poultry research facilities, University of Arkansas, Fayetteville, AR from
April 2, 1984 to May 21, 1984. The experiment consisted of four dietary
treatments which were monensin at 110 g/ton, monensin at 110 g/ton plus
bacitracin zinc at 50 g/ton, monensin at 110 g/ton plus roxarsone at 45.4 g/ton
and monensin at 110 g/ton plus bacitracin zinc at 50 g/ton plus roxarsone at
45.4 g/ton. One thousand four hundred and forty day-old, sexed broiler chickens
from a commercial hatchery were placed randomly by sex in 24 pens to provide 30
male and 30 female chicks per pen. Treatments were randomly assigned to blocks
of pens. Each 7' x 8' pen was equipped with two hanging tube-type feeders, an
automatic water fount and an infrared brooder. During the first 7 days
supplemental feed and water were available.
Summary of Floor-Pen Studies
The three described floor-pen studies, using approved protocols and 5,640
broiler chickens (equal numbers of males and females), were conducted under
conditions simulating actual field use to determine the growth promoting
effects of bacitracin zinc and roxarsone in combination with monensin sodium.
The studies were conducted in three different geographical locations.
Consistent with pen size and allowing 0.8 to 0.9 square feet per bird, 50 to
100 birds of equal sex were selected at random and assigned to pens. Six or
seven replicates were used per treatment group. Bacitracin zinc at 0 and 50
grams per ton of feed was used in combination with roxarsone at 0 or 45.4 g/ton
of feed to provide all 4 of the possible combinations of these drugs. Monensin
sodium at 110 grams per ton of feed was used in all feed in each study. The
studies were designed and conducted to simulate varying conditions as climate,
geographical location, weather, management practices, and degree of disease
contamination of the premises.
Feed consumption was corrected for mortality by estimating feed consumed from
standard tables based on age of each bird when it died in each pen and
subtracting that amount from the total feed consumed by that pen.
A detailed statistical evaluation of the three studies was conducted by Dr.
Charles Gates of the Institute of Statistics, Texas A&M University, College
Station, TX. The data were combined over the trials and analyzed using SAS's
GLM Procedures (*). A combined analysis of variance showed that the bacitracin
zinc significantly improved feed efficiency (P <0.01) independent of the
dose of roxarsone (Table 1). In addition, roxarsone significantly improved feed
efficiency (P <0.05) independent of the dose of bacitracin zinc.
Based on the results of specific treatment comparisons of data from the three
floor pen studies, this application qualifies for full range approval for the
three-way combination of bacitracin zinc, roxarsone and monensin under CVM
policy for combination drugs.
Based on the revised Drug Combination Guidelines, the data adequately
demonstrate the contribution of both bacitracin zinc and roxarsone on the feed
efficiency of broiler chickens and support the use of 4-50 grams bacitracin
zinc and 22.7-45.4 grams roxarsone per ton of feed for improved feed efficiency
in the presence of 90-110 grams monensin sodium per ton.
The claim for the combination is: "As an aid in the prevention of coccidiosis
caused by Eimeria necatrix, E. tenella, E. acervulina, E. brunetti, E.
maxima and E. mivati; and for improved feed efficiency."
* (SAS User's Guide: Statistics, 1982 Edition, SAS Institute, Cary, NC)Ed. note: The following table has 10 columns.
TABLE 1 Summary
of Response of Broilers to Bacitracin Zinc and/or Roxarsone When Fed With Monensin
Monensin, 110 g/ton Monensin, 110 g/ton Monensin, 110 g/ton Monensin, 100g/ton
plus BZN, 50g/ton plus BZN, 50 g/ton plus Roxarsone, 45.4 g/ton plus Roxarsone,
45.4 g/ton
No. Average Feed/ Average Feed/ Average Feed/ Average Feed/
Reps Weight Gain Weight Gain Weight Gain Weight Gain
TX-B-112-83 7 3.62 2.26 3.77 2.11 3.88 2.10 3.79 2.11
MO-B-I14-84 6 4.18 2.26 4.26 2.20 4.12 2.25 4.27 2.18
ARK-B-120-84 6 4.33 2.10 4.52 2.03 4.52 2.05 4.54 1.99
Average 4.04 2.20 4.18 2.11 4.17 2.13 4.20 2.09
Effectiveness - Non-interference Studies:
Two adequate and well controlled battery studies, using approved protocols and
400 Arbor Acres/Peterson broiler chickens, equal numbers of males and females,
were conducted in environmentally controlled animal rooms with even lighting
and power ventilation, located at the experimental poultry farm of the
University of Georgia, Department of Poultry Science, near Athens, GA.
Experiment No. GA-B-118-85; GA-B-118-85/2
Investigator:
Larry R. McDougald, Ph.D.
Department of Poultry Science
University of Georgia
Athens, GA 30602
Monitor:
Ralph V. Fell, Ph.D.
Route 9, Box 42
Pine Bluff, AR 71603
Each of eight treatments (see Table 2) were replicated with 4 cages of 10 wing
banded birds each (5 males and 5 females) in the two separate studies. The
birds were given unmedicated broiler starter until they were 12 days old, then
they were weighed, allocated to cages according to weight by means of a
Statistical Analysis System Program, and given medicated feed. At 14 days of
age, the birds were reweighed and infected with mixed cultures of coccidia. The
infective cultures were E. mitis, E. necatrix and E. brunetti in
Study la; and E. acervulina, E. maxima and E. tenella in Studies
lb and 2. The coccidia species that were used were recent isolates obtained
from commercial poultry farms in the United States.
Data, including death losses, intestinal lesion scores, droppings scores,
weight gain and feed consumption were recorded over the 2 weeks following
infection (Table 2). The infections reduced weight gains in the infected
controls, compared with the uninfected controls. Treatment with monensin was
effective in improving weight gain in all instances, whether it was used alone
or in combination with bacitracin zinc and/or roxarsone. Lesion scores were
recorded for the upper, mid and cecal areas of the gut. Monensin was
effective in controlling coccidiosis caused by the six species of
Eimeria in the broiler chickens. The use of bacitracin zinc and
roxarsone with monensin did not interfere with the anti-coccidial action of
monensin.
Ed. note: The following table has 14 columns.
TABLE 2
Anti-coccidial Activity of Monensin in Combination with Bacitracin Zinc and
Roxarsone Against Mixed Eimeria Infections in Young Broiler Chickens
Average Live Total Lesion Total Droppings
Weight (g) Mortality Scores/Bird Scores/Bird
Study Study Study Study Study Study Study Study Study Study Study Study
Medicated g/ton la 1b 2 la 1b 2 la 1b 2 la 1b 2
1. None, 0 461.4 441.7 454.9 0/40 0/40 0/40 0 0 0 0 0 0
uninfected
2. None 0 357.1 138.2 127.0 1/40 33/40 27/40 4.75 12.00 12.00 7.25 8.25 15.50
3. Monensin 90 389.7 303.4 412.1 0/40 6/40 2/40 0.69 5.50 5.30 0.75 4.00 9.25
4. Bacitracin 100 256.9 -- 100.8 2/40 -- 27/40 5.88 -- 12.00 5.00 -- 15.75
Zinc
5. Monensin + 90 358.6 -- 413.4 0/40 -- 2/40 0.88 -- 6.38 0.75 -- 9.25
Bacitracin 100
Zinc
6. Bacitracin
Zinc + 100 145.1 242.1 -- 0/40 21/40 -- 6.38 12.00 -- 5.00 6.75 --
Roxarsone 45
7. Monensin + 90 368.7 327.9 -- 0/40 5/40 -- 0.56 6.25 -- 0 2.00 --
Bacitracin
Zinc + 100
Roxarsone 45
8. Monensin + 90 427.8 399.7 -- 0/40 11/40 -- 0.69 6.50 -- 0.25 2.00 --
Roxarsone 45
Study la, infective cultures were from field isolates of E. mitis, E.
necatrix and E. brunetti (Study GA-B-118-85).
Study 1b, infective cultures were from field isolates of E. acervulina, E.
maxima and E. tenella (Study GA-B-l18-85).
Study 2, infective cultures were from field isolates of E. acervulina, E.
maxima and E. tenella (Study GA-B-I 18-85/2).
V. ANIMAL SAFETY
The basic animal safety data for the individual drugs may be found in the
original NADA 098-452 for bacitracin zinc, NADA 038-878 for monensin and NADA
007-891 for 3-Nitro (also MF 19 for roxarsone). The effectiveness studies shown
in Section IV demonstrate that no ill effects occurred when the drugs were
combined indicating that they are as safe when fed in combination as when fed
alone.
This application is in accord with the Animal Safety Guidelines. Additional
safety studies were not required because: (1) The drugs have been approved
singly and (2) adequate documentation has been provided to show that these
compounds are compatible in combination when used in broiler chicken feeds.
Therefore, based on the data in the original NADAs, the non-interference study,
the floor-pen efficacy studies, and the drug residue elimination study, it is
concluded that this combination of drugs may be safely fed to broiler
chickens.
VI. HUMAN SAFETY
It has been demonstrated in the original NADAs (098-452 for bacitracin
zinc, 038-878 for monensin and 007-891 for 3-Nitro) and in MF 19 for roxarsone
that these products are not a hazard to human health when used according
to approved labeling. Tolerances for residues of bacitracin zinc are established
at 0.5 ppm, negligible residue, in uncooked tissue of chickens (21 CFR 556.70).
Tolerances for arsenic in the edible tissues of chickens are established
at 0.5 ppm in muscle and 2 ppm in edible by-products (21 CFR 556.60). Tolerances
for residues of monensin in edible tissues of chickens are 0.05 ppm (21
CFR 556.420). The residue data supporting the individual uses of bacitracin
zinc, roxarsone and monensin have been presented in the original applications
for each.
Tissue Residue Studies
In the first tissue residue study (AEF-1-83) with monensin, roxarsone
and bacitracin zinc, the recovery of bacitracin from spiked control tissue
was below the acceptable level. A second tissue residue study (MO-B-TR-1-85)
was conducted to test for bacitracin residues.
Experiment A: AEF-1-83 (Monensin, B: MO-B-TR-1-85 (Bacitracin
Roxarsone) Zinc)
Investigator A: Thomas Kennedy, Ph.D. B: Randall A. Primo
AEF Research, Inc. Ponderosa Research Company
Waunakee, WI 53597 French Village, MO 63036
Monitor A: Cornell Johnson B: Ralph V. Fell, Ph.D.
5133 Caton Lane Route 9, Box 42
Waunakee, WI 53597 Pine Bluff, AR 71603
Both residue studies were conducted in a similar manner. Commercial broiler
chicks were divided into two groups containing equal numbers of each sex.
One group was maintained on a non-medicated broiler feed to provide control
tissues for drug recovery and non-interference studies. The other group
was fed the same basal feed medicated with monensin at 110 g/ton, roxarsone
at 45.4 g/ton and bacitracin zinc at 100 g/ton. Birds remained on test until
at least 48 days of age after which some birds were withdrawn from medicated
diet for 0, 1, 2, 3 or 5 days. The weight gains and feed efficiencies of
the birds in both studies were similar to the weight gains and feed efficiencies
obtained in the broiler industry. Birds of each sex were randomly selected
and sacrificed for each drug to be assayed and for each withdrawal time.
Chickens were processed in a manner similar to commercial practices. Tissue
samples were removed from each bird and placed in individual plastic tissue
bags and labeled for treatment, chicken number, sex, tissue and days withdrawn
from drugs. All tissues were quick frozen and shipped on dry ice to the
analytical laboratories for drug assay.
The summary of the tissue residue depletion studies are shown in Table
3. These data establish that each drug in the presence of the other two
drugs does not exceed its established safe concentration or tolerance.
Tissue assay non-interference and method validation studies for bacitracin
zinc tissue assay were conducted by spiking control samples with bacitracin
zinc, roxarsone and monensin and then assaying for bacitracin residues.
The assay results demonstrated no interference by monensin and roxarsone
for bacitracin (MO-B-TR-1).
A non-interference study for monensin was conducted by spiking control
tissue samples with monensin, roxarsone and bacitracin zinc and then assaying
these tissues for monensin content. The results demonstrated no interference
by bacitracin zinc and roxarsone for monensin.
Assay non-interference data are not required for roxarsone due to the
procedure for arsenic analysis.
TABLE 3
Residue Depletion Assay Results
Tissue
Liver Kidney Skin/Fat Muscle
Monensin (AEF-1-83)
Established safe concentration, ppm -- -- 0.05 --
Monensin residue:
2-day withdrawal No detectable residue
3-day withdrawal No detectable residue
Bacitracin Zinc (MO-B-TR-1-85)
Established tolerance, ppm -- -- -- 0.5
Bacitracin residue:
0-day withdrawal No detectable residue
l-day withdrawal No detectable residue
Roxarsone (AEF-1-83)
Established tolerance, ppm 2.0 2.0 2.0 0.5
Roxarsone residue:
0-day withdrawal 1.0 0.7 0.3 0.2
3-day withdrawal 0.5 0.3 0.1 0.1
5-day withdrawal 0.4 0.3 0.1 0.1
Monensin Assay Procedure No. 5801450 for chicken tissues and eggs. Eli
Lilly and Company, Greenfield Laboratories, Greenfield, IN.
Bacitracin Assay Procedure from Antibiotic Residues in Milk, Dairy
Products and Animal Tissues, Methods, Reports and Protocols, Rev. October 1968.
National Center for Antibiotic and Insulin Analysis. Food and Drug
Administration, Department of Health, Education and Welfare, Washington, DC
20204.
Arsenic Assay Procedure No. 5801380 for chicken tissues essentially as
described in Official Methods of Analyses of Association of Official Analytical
Chemists, 11th Edition, p 402 (1970).
Based upon the established withdrawal times for monensin, bacitracin zinc
and roxarsone, no residues were above tolerances in any tissues from these
broiler chickens. The data support a 5-day withdrawal period for the bacitracin
zinc, monensin, roxarsone combination because of the required 5-day withdrawal
period for roxarsone.
VII. AGENCY CONCLUSIONS
The data submitted in support of this NADA comply with the requirements
of Section 512 of the Act and demonstrate that monensin (90-110 g/ton) plus
bacitracin zinc (4-50 g/ton) plus roxarsone (22.7-45.4 g/ton) are safe and
effective for the claims indicated in Section II of this FOI summary.
This original NADA is regarded as a Category II application under CVM's
supplemental policy (42 FR 64367) which did not require reevaluation of
safety and efficacy data in the parent NADAs. The drugs are to be supplied
to the feed mill in individual premixes for combining in finished feeds
(Type C Article) within the indications and dosages approved in the parent
NADAs.
Residue depletion studies demonstrate that monensin, bacitracin zinc and
roxarsone deplete to levels well below tolerance levels within the required
five days withdrawal time before the birds are slaughtered. See Table 3
for residue depletion assay results and tolerance levels.
Non interference studies demonstrated that monensin prevented an outbreak
of coccidiosis alone and in the presence of bacitracin zinc and roxarsone
when the birds were exposed to the six major species of Eimeria.
The data from three well controlled floor pen studies demonstrate the effectiveness
of bacitracin zinc (50 g/ton) .and of roxarsone (45.4 g/ton) in the presence
of monensin (110 g/ton). These data qualify the application for approval
under CVM's policy outlined in the combination drug guidelines revised October
1983. This policy permits the granting of range approval for bacitracin
zinc (4-50 g/ton) plus roxarsone (22.7-45.4 g/ton) plus monensin (90-110
g/ton) as an aid in the prevention of coccidiosis and for improved feed
efficiency in broiler chickens as shown in Section II of this FOI Summary.
VIII. LABELING (Attached)
Copies of applicable labels may be obtained by writing to the:
Food and Drug Administration
Freedom of Information Staff (HFI-35)
5600 Fishers Lane
Rockville, MD 20857
Or requests may be sent via fax to: (301) 443-1726. If there are problems sending a fax, call (301) 443-2414.
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